GRK-D5s belong to an increasing number of kinases involved in the regulation of G-protein coupled receptors (beta 2, alpha 2 adrenergic, muscarinic). The mu opioid receptor also belongs to the superfamily of G-protein coupled receptors. The delta opioid receptor has been shown to be phosphorylated by GRK 2. Therefore, GRK 2 may be also involved in the phosphorylation of the mu opioid receptor and subsequently in narcotic tolerance and dependence. Thus, selective inhibitors of GRK 2 are very valuable although not yet available. We established a molecular model of the catalytic site of GRK 2. This model is derived from the crystal structure of the catalytic subunit of cAMP dependent protein kinase (PKA) by homology modeling. After a sequence alignment (31% homology identity for the catalytic domain), we swapped the differing amino acids using MidasPlus. In collaboration with Dan Gschwend, molecular docking of a chemical database was performed with DOCK. Meanwhile, we have established a biochemical assay for GRK 2 in our lab. We just started testing the compounds which scored best for GRK 2 but relatively poor for PKA. The next step will be to correlate the biochemical results with the modeling results in order to validate our GRK model. In order to interpret and present our data, we have to look at the most likely binding of good inhibitors to the catalytic site of GRK 2 (which amino acids are involved) and how those inhibitors compete with the ATP binding site. We need MidasPlus in order to display/printout the interaction of inhibitors with the catalytic site and in particular with the ATP binding site. A paper in that project is in preparation. Altogether, the homology modeling and display of a GRK 2 model using MidasPlus is an important part of our project to find inhibitors of GRK 2 in order to understand the role of GRK2 in the regulation of the mu opioid receptor.